Hilar mossy cells regulate network function in the hippocampus through both direct excitation and di-synaptic inhibition of dentate granule cells (DGCs). Substantial mossy cell loss accompanies hippocampal circuit changes in epilepsy. We examined the contribution of surviving mossy cells to network activity in the reorganized dentate gyrus after pilocarpine-induced status epilepticus. To examine functional circuit changes, we optogenetically stimulated mossy cells in acute hippocampal slices from male mice. In control mice, activation of mossy cells produced monosynaptic excitatory and di-synaptic GABAergic currents in DGCs. In pilocarpine-treated mice, mossy cell density and excitation of DGCs were reduced in parallel, with only a minimal reduction in feedforward inhibition, enhancing the inhibition:excitation ratio. Surprisingly, mossy cell-driven excitation of parvalbumin-positive basket cells, primary mediators of feed-forward inhibition, was maintained. Our results suggest that mossy cell outputs reor...

Inhibitory microcircuits play an essential role in regulating cortical responses to sensory stimuli. Interneurons that inhibit dendritic or somatic integration act as gatekeepers for neural activity, synaptic plasticity and the formation of sensory representations. Conversely, interneurons that selectively inhibit other interneurons can open gates through disinhibition. In the anterior piriform cortex (APC), relief of inhibition permits associative long-term potentiation (LTP) of excitatory synapses between pyramidal neurons. However, the interneurons and circuits mediating disinhibition have not been elucidated. In this study, we use an optogenetic approach in mice of both sexes to identify the inhibitory interneurons and disinhibitory circuits that regulate LTP. We focused on three prominent interneuron classes- somatostatin (SST), parvalbumin (PV), and vasoactive intestinal polypeptide (VIP) interneurons. We find that LTP is gated by the inactivation SST or PV interneurons and by the activation of VIP i...

Neural phase-locking to temporal fluctuations is a fundamental and unique mechanism by which acoustic information is encoded by the auditory system. The perceptual role of this metabolically expensive mechanism, the neural phase-locking to temporal fine structure (TFS) in particular, is debated. Although hypothesized, it is unclear if auditory perceptual deficits in certain clinical populations are attributable to deficits in TFS coding. Efforts to uncover the role of TFS have been impeded by the fact that there are no established assays for quantifying the fidelity of TFS coding at the individual level. While many candidates have been proposed, for an assay to be useful, it should not only intrinsically depend on TFS coding, but should also have the property that individual differences in the assay reflect TFS coding per se over and beyond other sources of variance. Here, we evaluate a range of behavioral and electroencephalogram (EEG)-based measures as candidate individualized measures of TFS sensitivity...

Abnormal levels of acoustic activity can result in hearing problems such as tinnitus and language processing disorders, but the underlying cellular and synaptic changes triggered by abnormal activity are not well understood. To address this issue, we studied the time course of activity-dependent changes that occur at auditory nerve synapses in mice of both sexes after noise exposure and conductive hearing loss. We found that EPSC amplitude and synaptic depression decreased within two days of noise exposure, through a decrease in the probability of vesicle release ( P r). This was followed by a gradual increase in EPSC amplitude, through a larger pool of releasable vesicles ( N ). Occlusion of the ear canal led to a rapid decrease in EPSC amplitude, through a decrease in N , which was followed by an increase in EPSC amplitude and synaptic depression through an increase in P r. After returning to normal sound levels, synaptic depression recovered to control levels within 1 to 2 d. However, repeated exposure ...

The architecture of the efferent auditory system enables prioritization of strongly overlapping spatiotemporal cochlear activation patterns elicited by relevant and irrelevant inputs. So far, attempts at finding such attentional modulations of cochlear activity delivered indirect insights in humans or required direct recordings in animals. The extent to which spiral ganglion cells forming the human auditory nerve are sensitive to selective attention remains largely unknown. We investigated this question by testing the effects of attending to either the auditory or visual modality in human cochlear implant (CI) users (3 female, 13 male). Auditory nerve activity was directly recorded with standard CIs during a silent (anticipatory) cue-target interval. When attending the upcoming auditory input, ongoing auditory nerve activity within the theta range (5-8 Hz) was enhanced. Crucially, using the broadband signal (4-25 Hz), a classifier was even able to decode the attended modality from single-trial data. Follow...

Response nonlinearities are ubiquitous throughout the brain, especially within sensory cortices where changes in stimulus intensity typically produce compressed responses. Although this relationship is well established in electrophysiological measurements, it remains controversial whether the same nonlinearities hold for population-based measurements obtained with human fMRI. We propose that these purported disparities are not contingent on measurement type and are instead largely dependent on the visual system state at the time of interrogation. We show that deploying a contrast adaptation paradigm permits reliable measurements of saturating sigmoidal contrast response functions (10 participants, 7 female). When not controlling the adaptation state, our results coincide with previous fMRI studies, yielding nonsaturating, largely linear contrast responses. These findings highlight the important role of adaptation in manifesting measurable nonlinear responses within human visual cortex, reconciling discrepa...

Primates explore their visual environment by making frequent saccades, discrete and ballistic eye movements that direct the fovea to specific regions of interest. Saccades produce large and rapid changes in input. The magnitude of these changes and the limited signaling range of visual neurons mean that effective encoding requires rapid adaptation. Here, we explore how macaque cone photoreceptors maintain sensitivity under these conditions. Adaptation makes cone responses to naturalistic stimuli highly nonlinear and dependent on stimulus history. Such responses cannot be explained by linear or linear-nonlinear models but are well explained by a biophysical model of phototransduction based on well-established biochemical interactions. The resulting model can predict cone responses to a broad range of stimuli and enables the design of stimuli that elicit specific (e.g., linear) cone photocurrents. These advances will provide a foundation for investigating the contributions of cone phototransduction and post-...

There are two distinct sources of retinal image motion: objects moving in the world and observer movement. When the eyes move to track a target of interest, the retinal velocity of some object in the scene will depend on both eye velocity and that object's motion in the world. Thus, to compute the object's velocity relative to the head, a coordinate transformation must be performed by vectorially adding eye velocity and retinal velocity. In contrast, a very different interaction between retinal and eye velocity signals has been proposed to underlie estimation of depth from motion parallax, which involves computing the ratio of retinal and eye velocities. We examined how neurons in the middle temporal (MT) area of male macaques combine eye velocity and retinal velocity, to test whether this interaction is more consistent with a partial coordinate transformation (for computing head-centered object motion) or a multiplicative gain interaction (for computing depth from motion parallax). We find that some MT ne...

Amanda Jiménez-Pompa, Sara Sanz-Lázaro, Romidan Ewere Omodolor, José Medina-Polo, Carmen González-Enguita, et al. (see pages [1173–1183][1]) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels with roles throughout the CNS and peripheral nervous system, as well as in